Abstract

The epidemiology of severe acute renal failure has dramatically changed in the past
decade. Its leading cause is sepsis and the syndrome develops mostly in the intensive
care unit as part of multiple organ dysfunction syndrome. After the significant improvements
obtained from the mid 1970s to the mid 1990s, the past decade has seen a dramatic
evolution in technology leading to new machines and new techniques for renal and multiple
organ support. Extracorporeal therapies are now performed using adequate treatment
doses, which have resulted in improved survival in the general population. At the
same time, patients with sepsis seem to benefit from the use of increased doses, as
in the case of high-volume hemofiltration or of increased membrane permeability and
sorbents as in the case of continuous plasmafiltration adsorption. The humoral theory
of sepsis and the peak concentration hypothesis have spurred a significant interest
in the use of such extracorporeal therapies for renal support and possibly for the
therapy of sepsis. Ongoing research and prospective studies will further elucidate
the role of such therapies in this setting.

Commentary

In the past decade, the change in the epidemiology of acute renal failure has made
critical care nephrology an emerging sub-speciality of intensive care medicine. Dedicated
literature and a series of physicians and nurses have made an effort to bridge the
knowledge and experience from nephrology and critical care medicine in response to
an increased incidence of acute kidney injury in intensive care unit (ICU) patients
[1].

The origin of this process can definitely be found in the mid 1970s, when continuous
arteriovenous hemofiltration (CAVH) appeared on the scene. CAVH has been a tool that
has permitted the treatment of patients with acute kidney injury in which peritoneal
dialysis or hemodialysis were clinically or technically precluded [2]. This opened the doors of ICUs to a dedicated dialysis technology that experienced
a flourishing evolution in subsequent years. Within a few years, continuous veno-venous
hemofiltration (CVVH) replaced CAVH because of its improved performance and safety.
The advance was made possible by the use of blood pumps, calibrated ultrafiltration
control systems and double lumen venous catheters. In the late 1980s, specific machines
for continuous renal replacement therapies (CRRTs) were designed and a new era of
renal replacement in the critically ill patient began [3]. The therapy started to be standardized and clear indications began to be defined.

The evolution of technology did not stop, however, and the recent demand for higher
efficiency and exchange volumes has spurred new interest in a further generation of
machines with better performance, integrated information technology and easy to use
operator interfaces. An example of such technological evolution is represented by
the passage from CAVH systems to the BSM 22 and Prisma machines to the most recently
developed Prismaflex machine (Gambro Dasco, Mirandola, Italy; Fig. 1). A schematic drawing of different techniques available today for the therapy of
the critically ill patient with renal and other organ dysfunction is given in Fig.
2. The last generation of machines available on the market today and representing the
evolution of the past decade of research and development is shown in Fig. 3.

Figure 3. The last generation of machines available on the market for continuous renal replacement
therapy.

Two interesting aspects of the evolution of renal replacement therapy (RRT) in the
ICU over the past decade are represented by the definition of an 'adequate' dose of
dialysis in acute kidney injury and the potential of high dose therapies for the treatment
of sepsis [4]. The first of these has identified 35 ml/kg/h as a dose of dialysis capable of improving
survival, whereas higher doses do not seem to give additional benefits in the general
population [4]. The second concept introduces the rationale for high-volume hemofiltration (HVHF)
in patients with acute renal failure and sepsis [5]. In this setting, the most important advance of the past decade has been the use
of either increased exchange volumes in hemofiltration, or the combined use of adsorbent
techniques in systems where the cut-off of the membrane was increased to the level
commonly seen in membranes for plasmafiltration [6]. HVHF is a variant of CVVH that requires higher surface area hemofilters and employs
ultrafiltration volumes of 35 to 80 ml/kg/h.

This technique is associated with practical problems, including the requirement of
adequate hardware, significant amounts of re-infusion fluid and monitoring systems
accurate enough for the high volumes exchanged and the relatively high blood flows
used.

In the past five years, many studies have been conducted to evaluate and demonstrate
benefits of increasing the volume of ultrafiltration and replacement fluid during
CRRT [7,8], particularly in complex and very severe syndromes such as severe sepsis and septic
shock, associated or not with acute renal failure.

In general, the high-volume approach provides higher clearances for middle/high molecular
weight solutes than a simple diffusive transport (CVVHD) or a convection-based transport
at lower volumes (CVVH). These solutes seem to be primarily involved in the systemic
inflammatory response syndrome, which characterizes the sepsis syndrome, and their
efficient removal may thus be beneficial [9].

Alternative approaches have been based on more efficient removal of inflammatory mediators
by high cut-off hemofilters, which are characterized by an increased effective pore
size. Most commercially available hemofilters do not permit a substantial elimination
of cytokines because of the low cut-off point of their membranes. The use of high
cut-off hemofilters is a new and effective approach to cytokine removal, but it has
potentially harmful side effects, such as the loss of essential proteins like albumin
[10]. To prevent this side effect, plasmafiltration coupled with adsorption (CPFA) has
been designed and experimentally used with beneficial effects in septic patients [11]. CPFA is a combined therapy in which plasma is separated from blood and circulated
through a sorbent bed. After this purification phase, blood is reconstituted and dialyzed
with standard techniques. The final effect is an increased removal of protein bound
solutes and large molecular weight toxins.

These therapies are not selective in removing specific mediators (pro- and anti-inflammatory
mediators are equally removed) and, consequently, their role is not completely understood
and their usefulness remains the subject of much debate. Early data are encouraging
but additional data are required before they could become part of the standard management
of sepsis. More statistically powered studies are needed to confirm the preliminary
results on the positive effect of HVHF and CPFA on outcome. Except for the beneficial
effect of dialysis dose, no randomised trial has evaluated the effect of HVHF on clinical
outcome, or the effect of different modalities of CRRT on length of stay and recovery
of renal function in patients with sepsis. This research is needed. Adequate technical
support becomes mandatory, therefore, to fulfil all these expectations. The evolution
of understanding of the above mentioned concepts has led to the improvement of technology
and the generation of new machines and devices compatible with the demand for increased
efficiency, accuracy, safety, performance and cost/benefit ratio.

At present, almost all CRRT therapies can be delivered in a safe, adequate and flexible
way, thanks to devices specifically designed for critically ill patients to a point
that multiple organ support therapy is envisaged as a possible therapeutic approach
in the critical care setting [12].

HVHF or CPFA can be seen as a potent powerful immuno-modulatory treatment in sepsis.
Since sepsis and systemic inflammatory response syndrome are characterized by a cytokine
network that is synergistic, redundant, autocatalytic and self-augmenting, the control
of such a non-linear system can not be approached by simple blockade or elimination
of some specific mediators. Therefore, non-specific removal of a broad range of inflammatory
mediators by HVHF and CPFA may be beneficial, as recently suggested on the basis of
the 'peak concentration' hypothesis [9].

The high dose that characterizes HVHF can be delivered either using a constantly high
exchange rate or by delivering a 'pulse' (for 6 to 8 h) of very high-volume hemofiltration
(85 to 100 ml/kg/h) followed by standard doses [13]. In both cases, cytokine half-lives and concentrations are affected, the first by
the continuous modality and the second by the non-specific decapitation of peaks.
Therefore, rather than a detailed analysis of each molecule involved, we envisage
as much more interesting and useful a teleological analysis of the impact of HVHF
on more integrated events such as monocyte cell responsiveness, including apoptosis,
neutrophil priming activity and oxidative burst [14-16]. More studies are needed to define its role in hyperdynamic septic shock, with or
without acute renal failure. A last comment should be dedicated to the use of sorbents
and especially those cartridges dedicated to the adsorption of endotoxin and related
material. A great deal of evolution has occurred in this field but it seems we are
only at the beginning of a long and possibly fruitful journey [16].

At the end of this commentary we might speculate that although improvements have been
made, a lot remains to be done. For sure, the progress of technology in critical care
nephrology has been enormous and more will come in the near future.